Role of development signaling pathways in testicular physiology and spermatogenesis

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Spermatogenesis, the process by which mature sperm cells are produced in the testis, is one of the most complex processes that occur in the body and is essential for sexual reproduction. Spermatogenesis consists of a carefully orchestrated series of events beginning with the asymmetrical division of spermatogonia (the germ cell stem cell population), followed by meiosis to produce haploid spermatids, and finally the differentiation of the spermatids into mature spermatozoa, the latter process being commonly referred to as spermiogenesis. While our knowledge of the molecular mechanisms that regulate and coordinate spermatogenesis remains incomplete, it is well established that androgens are critical effectors, and these androgens are produced locally within the testis by Leydig cells. Far from being a static population, Leydig cells arise and are continuously renewed from a mesenchymal precursor cell type located in the testis interstitium. Therefore, spermatogenesis and Leydig cell function both depend on the precise regulation of the proliferation and differentiation of two distinct stem/progenitor cell populations. Our preliminary data, coupled to a handful of recent studies, suggest that a family of signaling molecules called Wnts may play major roles in both cell types, functioning as regulators of both Leydig cell proliferation and spermiogenesis. In light of this, we propose 1) to identify the specific Wnt pathway components that mediate Wnt signaling in the testis; 2) to study the effects of disrupting or increasing testicular Wnt signaling in a cell-specific manner in vivo; and 3) to identify the downstream transcriptional targets of Wnt signaling in Leydig cells. Taken together, these studies should unearth previously unsuspected mechanisms of regulation of some very fundamental aspects of testicular physiology, and will further our understanding of male fertility and of stem/progenitor cell biology.